"Finding out more about what drives cancer cell homing, colonization and proliferation in bone is key to improving the outcome for these poor-prognosis patients," explains Nicola Brown, a vascular biologist based at the University of Sheffield, UK. "The mechanical properties of the bone micro-environment are hugely important, but have been largely disregarded until now because of the difficulty in making the necessary measurements."

To generate much-needed data, Brown and her co-investigator Jamie Hobbs – an expert in scanning probe microscopy – are combining biological and mechanical approaches with theoretical physics modelling. The result will be the first comprehensive characterization of the mechano-biological features of the bone microenvironment in breast cancer bone metastasis. Funding for this pioneering work is provided by Cancer Research UK and the EPSRC via their co-funded Multidisciplinary Project Award.

Mechanical factors

Drugs that modify the biomechanical properties of bone when used in combination with current standard regimes could play a major role in boosting the long-term survival rates of breast cancer patients. What's more, the strategy could also be relevant to other tumour types associated with skeletal metastasis, including prostate and lung cancers.

Hobbs and Brown first teamed-up as co-supervisors of a three-year PhD project focusing on whether breast cancer cells were mechanically different to normal cells, which led them towards making measurements on tissue. "We felt that the next really challenging step was to mechanically map the regions of bone where we know the metastatic breast cancer cells colonize," says Brown.

Specifically, the researchers want to find out whether there are mechanical factors that encourage cancer to seek out bone in the first place and contribute to its successful proliferation. How do cancer cells, for example, respond to the mechano-biology of their micro-environment in order to proliferate and produce secondary tumours or lie dormant?

Completing the characterization will put the scientists in a strong position to tie together the nanomechanical and biological properties of the so-called bone metastatic niche – exploring conditions of cancer growth and therapeutic intervention.

Knowledge exchange

Multi-disciplinary interaction is a key theme to the project and is actively encouraged by the funding format. "It's a way of educating biologists in physical techniques and principles and vice versa," Brown comments.

Working together, the team has adapted an atomic force microscope (AFM) to begin mapping bone surfaces in high resolution; building up a detailed picture of the key mechanical characteristics of the micro-environment.

Initially, the researchers are focusing on samples that are free of cancer cells to determine baseline values for the tissue. One of the major challenges has been in cleaving the bone so that the sample can be accurately profiled by the AFM's stylus. "Over the past six months, we've tried a number of different approaches and the process is now sufficiently optimized to give us some interesting data, which is encouraging" adds Brown.

Planned upgrades to the instrument include adding optical guidance, which will make it easier to locate the AFM on areas of interest such as blood vessels or the growth plate. At the same time, the group has recruited mathematicians into the team who are interested in modelling cancer cell mechanics.

Numerical expressions generated by the researchers and fed with experimental data, will contribute by highlighting further opportunities for manipulating the bio-physical aspects of the cancer-bone interaction to help combat secondary tumours.

The team includes Nicola Brown (vascular/tumour biology), Jamie Hobbs (biophysics), Ingunn Holen (bone/tumour biology), Rhoda Hawkins (mathematics), Keith Hunter (histopathology), Ashley Cadby (biophysics), Russell Hughes (tumour biology – researcher), Xinyue Chen (biophysics – researcher) and Natasha Cowley (mathematics – postgraduate student).

• This article is the second in a series looking at some of the research funded through the CRUK–EPSRC Multidisciplinary Project Award. In addition to this scheme, Cancer Research UK offers a range of funding opportunities open to researchers not currently working in cancer who are seeking to focus their expertise to this area: Pioneer Award; Early Detection Programme and Project Awards; and Grand Challenge.

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